In inhalation therapy, a pharmaceutical delivery device, such as a dry powder inhaler (“DPI”), is typically employed to deliver a prescribed dose of a pharmaceutical composition and, hence, medicament to the pulmonary system of a patient. The active compound must be inhalable. In order to be able to pass into the lungs, it must be present in particles of size about 0.5 to 10 μm. Such particles can be obtained, for example, by micronization, controlled precipitation from suitable solvents or by spray drying if the process conditions are suitably selected, controlled and carried out. In a typical DPI, a dose of the pharmaceutical composition is positioned in an aerosolization chamber, where it is aerosolized and, hence, dispersed into respirable particles by airflow supplied by the patient's inspiration effort. It is also well known in the art that in order to settle in the appropriate regions of the lung associated with local and/or systemic drug delivery, the dispersed particles must be of suitable size.
The pulmonary system includes the upper airways, including the oropharynx and larynx, followed by the lower airways, which include the trachea followed by bifurcations into bronchi and bronchioli. The upper and lower airways are called the conducting airways. The terminal bronchioli then divide into respiratory bronchioli, which then lead to the alveolar region, or the deep lung.
It is well known that medicament particles deposit in specific areas of the pulmonary system based upon the aerodynamic size of the particles and the flow rate of the air within which they are entrained. Typically, with average inhalation flow rates of between 30 and 90 liters per minute, particles having an aerodynamic diameter in the range of 0.5 to 3 μm are suitable for systemic delivery, as these particles deposit selectively in the deep lung. As mentioned above, particles having an aerodynamic diameter in the range of approximately 0.5 to 10 μm are suitable for local lung delivery.
Particles having an aerodynamic diameter greater than 10 um generally deposit in the mouth, throat or upper airways, offering little therapeutic benefit. Particles having an aerodynamic diameter less than 0.5 μm do not settle out of the air flow to deposit in the lungs, and are subsequently respired when the patient exhales.
The size or diameter of the particles, thus, is crucial for the therapeutic effect of a pharmaceutical composition for inhalation. Efforts in this area have included the use of excipients, such as milled or micronized lactose, to dilute the medicament in the pharmaceutical composition, allowing microgram quantities of very potent medicaments to be precisely metered into milligram sized doses with an acceptable degree of control. By controlling the size ranges of the excipient powders, gains have been reported in flowability, dispersability and aerosolization of dry powder medicament formulations.
In an effort to increase the aerodynamic properties (aerosolizibility and dispersability) of the particles delivered to the selected target region of the lungs, recent efforts have led to a departure from the use of medicament particles milled to respirable size and then blended with excipient carriers.
For example, according to WO 99/16419, prior art compositions containing milled respirable drug particles and large excipient carrier particle systems may allow for at least some medicament particles to loosely bind to the surface of the large carrier surface and disengage upon inhalation, but a substantial amount of the medicament fails to disengage from the large lactose particles and is deposited in the throat. To allow undesirable throat deposition to be reduced, WO 99/16419 discloses microporous microparticles containing a medicament, an excipient (i.e. lactose) and surfactant.
WO03/024396 discloses a pharmaceutical composition comprising a medicament fraction of medicament particles having a mass median aerodynamic diameter no greater than approximately 10 μm; and at least 50% of a non-respirable excipient fraction, said non-respirable excipient fraction comprising low density excipient particles having an aerodynamic diameter greater than approximately 10 μm and a geometric diameter greater than approximately 30 μm.
US 2005/175549 discloses an inhalable dry powder mixture comprising effective amounts of two API's, optionally together with a pharmaceutically acceptable carrier. The carrier might be finely divided and may be selected from sugars such as lactose. However, there is no indication to use different particle sizes for the respective carrier and there is no indication that the relation of the carriers in the composition may be used to set specific characteristics of the inhalable mixture.
In pharmaceutical compositions for inhalation with two or more active substances, the tuning of the aerodynamic diameters is problematic. The aerodynamic diameter of a formulation is a parameter, which determines how deep the particles will intrude into the respiratory tract: the smaller it is the deeper the particles will enter. The tuning of the aerodynamic diameter of the inhaled formulation is needed to ensure the intrusion of the active ingredient into the desired part of the respiratory tract to unfold its full potential.
Especially with two or more active substances, which possibly should have different desired depth of intrusion into the respiratory tract, the tuning is very difficult, because of interactions between excipients with active substances and active substances with each other. With common preparation techniques for inhalation compositions the tuning can not be adjusted properly, because the arrangement of the adherence of active ingredients at the excipient carrier is quite randomly.
Since there is a growing demand for inhalation compositions for use in combination therapy involving two or more active agents, the development of new formulations providing a tailored administration of different inhalable drugs at one time to a patient in a precise and uniform amount is highly needed.